Adalimumab May Be Helpful for Juvenile Rheumatoid Arthritis

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Adalimumab May Be Helpful for Juvenile Rheumatoid Arthritis

http://www.medscape.com/viewarticle/579539

August 25, 2008 - Adalimumab may be effective for the treatment of children

with juvenile rheumatoid arthritis, according to the results of a study

reported in the August 21 issue of the New England Journal of Medicine.

" Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid

arthritis, " write J. Lovell, MD, MPH, at Cincinnati Children's

Hospital Medical Center in Ohio, and colleagues from the Pediatric

Rheumatology Collaborative Study Group and the Pediatric Rheumatology

International Trials Organisation.

" We evaluated the efficacy and safety of adalimumab, a fully human

monoclonal anti-TNF antibody, in children with polyarticular-course juvenile

rheumatoid arthritis. "

Participants in this study were patients aged 4 to 17 years with active

juvenile rheumatoid arthritis who had previously been treated with

nonsteroidal anti-inflammatory drugs. They were stratified based on

methotrexate use and treated with adalimumab, 24 mg/m2 of body-surface area

(maximal dose, 40 mg) subcutaneously every other week for 16 weeks. At week

16, patients with an American College of Rheumatology Pediatric 30% (ACR

Pedi 30) response were randomly assigned to receive adalimumab or placebo in

a double-blind fashion every other week for up to 32 weeks. The main

endpoint was disease flares.

At week 16, there were 74% of patients not receiving methotrexate (64/86)

and 94% of those receiving methotrexate (80/85) who had an ACR Pedi 30

response and were eligible for double-blind treatment. In patients not

receiving methotrexate, 43% of those receiving adalimumab and 71% of those

receiving placebo had disease flares (P = .03). In patients treated with

methotrexate, 37% of those receiving adalimumab and 65% of those receiving

placebo had disease flares (P = .02).

At 48 weeks, the proportion of patients receiving methotrexate who had ACR

Pedi 30, 50, or 70 responses were significantly greater for those receiving

adalimumab vs those receiving placebo. In patients not treated with

methotrexate, differences between those who received adalimumab and those

who received placebo were not significant. After 104 weeks of treatment,

response rates were sustained. Fourteen patients were reported to have

serious adverse events possibly related to adalimumab.

Limitations of this study include insufficient power to detect differences

between patients receiving and those not receiving methotrexate and sample

size and duration insufficient to determine the risks for rare adverse

events.

" Adalimumab therapy seems to be an efficacious option for the treatment of

children with juvenile rheumatoid arthritis, " the study authors write.

" Responses were sustained through 2 years of continued treatment. "

Abbott Laboratories supported this study and employs 3 of the study authors.

Ten of the study authors have disclosed various financial relationships with

Abbott Laboratories, Genzyme, Regeneron, Bristol-Myers Squibb, Hoffmann-La

Roche, Pfizer, Centocor, Amgen, Novartis, Xoma, Immunex, Wyeth

Pharmaceuticals, Talecris, Barr Pharmaceuticals, and/or Essex

Pharmaceuticals. The remaining study authors have disclosed no relevant

financial relationships.

N Engl J Med. 2008;359:810-820.

Clinical Context

The most common rheumatic disease in children is juvenile rheumatoid

arthritis, according to Ravelli and i in the March 3, 2007, issue of

The Lancet. Methotrexate treatment has been used for adults and children

with rheumatoid arthritis. Another treatment of adult rheumatoid arthritis

is adalimumab, a human, immunoglobulin 2 monoclonal anti-tumor necrosis

factor antibody. Keystone and colleagues reported in the May 2004 issue of

Arthritis and Rheumatism that adalimumab with or without methotrexate is

effective in the treatment of adult rheumatoid arthritis.

This randomized, double-blind, stratified, placebo-controlled, multicenter

study evaluates the efficacy and safety of adalimumab treatment of

polyarticular juvenile rheumatoid arthritis, using a 16-week open-label

lead-in phase, 32-week double-blind withdrawal phase, and open-label

extension phase.

Study Highlights

171 children aged 4 to 17 years with active polyarticular juvenile

rheumatoid arthritis and inadequate response to nonsteroidal

anti-inflammatory drugs were stratified based on methotrexate use in the

16-week open-label lead-in phase.

Active disease was defined by at least 5 swollen joints and at least 3

joints with limitation of motion.

Exclusion criteria were significant hematologic, hepatic, or renal

conditions; infection; recent live or attenuated vaccine administration; or

recent treatment with intravenous immune globulin, cytotoxic agents,

investigational drugs, disease-modifying antirheumatic drugs (excluding

methotrexate), or intra-articular, intramuscular, or intravenous

corticosteroids.

Nonsteroidal anti-inflammatory drugs, low-dose corticosteroids, and pain

medications (up to 12 hours before assessment) were permitted.

Visits occurred at screening, baseline, between days 2 and 10, weeks 2 and

4, and every 4 weeks through week 48 or withdrawal.

85 patients had received at least 10 mg/m2 of methotrexate per week in the

previous 3 months and continued to receive methotrexate during the 16-week

open-label phase and the 32-week withdrawal phase.

86 patients not receiving methotrexate had not received methotrexate at

least 2 weeks before study drug was started.

During the open-label phase, all subjects received adalimumab 24 mg/m2 of

body-surface area (up to 40 mg) subcutaneously every other week for 16

weeks.

At week 16, there were 74% of subjects receiving methotrexate and 94% of

subjects not receiving methotrexate who had an ACR Pedi 30 and entered the

32-week double-blind treatment phase.

Baseline characteristics for the 2 groups did not differ, but the group not

receiving methotrexate had shorter disease duration and greater number of

affected joints.

Of the methotrexate group, 37 were randomly assigned to placebo and 38 to

adalimumab subcutaneously every other week.

Of patients not receiving methotrexate, 28 were randomly assigned to placebo

and 30 to adalimumab.

Primary outcome measure was disease flare, defined by 30% or more worsening

in at least 3 of 6 core criteria for juvenile rheumatoid arthritis and 30%

or more improvement in no more than 1 criterion during double-blind phase

weeks 16 to 48.

Disease flares were less common in the adalimumab vs placebo group in

patients not receiving methotrexate (13 [43%] of 30 vs 20 [71%] of 28,

respectively; P = .03).

Disease flares were less common in the adalimumab vs placebo group in

patients receiving methotrexate (14 [37%] of 38 vs 24 [65%] of 37,

respectively; P = .02).

By week 48, ACR Pedi 30, 50, and 70 responses were more common in the

adalimumab vs placebo patients in the methotrexate group.

By week 48, ACR Pedi 30, 50, 70, and 90 responses were not significantly

different between adalimumab vs placebo patients in those not receiving

methotrexate.

In the open-label extension phase, all patients received adalimumab

subcutaneously every other week for 16 weeks and had visits every 8 weeks

for 1 year, then every 16 weeks.

ACR Pedi responses were maintained at 2 years.

The most common adverse events were infections and reactions at the

injection site.

Serious adverse events occurred in 14 patients receiving adalimumab vs 1

patient receiving placebo.

There were no reports of death, malignant conditions, opportunistic

infections, tuberculosis, demyelinating disease, or lupus-like reactions.

Limitations of the study included inadequate power to determine differences

between patients using or not using methotrexate and insufficient sample

size and study duration to assess risk for rare adverse events.

Pearls for Practice

In children with polyarticular juvenile rheumatoid arthritis, adalimumab

with or without methotrexate is more effective than placebo in reducing

disease flares, with response rates lasting up to 2 years.

Serious adverse events occurred in 14 children, possibly related to

adalimumab treatment, vs 1 child in the placebo group. The most common

adverse events are infections and reactions at the injection site.